RESEARCH
BMJ: first published as 10.1136/bmj-2022-071245 on 7 September 2022. Downloaded from http://www.bmj.com/ on 18 March 2024 by guest. Protected by copyright.
Prevention of covid-19 and other acute respiratory infections
with cod liver oil supplementation, a low dose vitamin D
supplement: quadruple blinded, randomised placebo
controlled trial
Sonja H Brunvoll,1 Anders B Nygaard,1 Merete Ellingjord-Dale,1 Petter Holland,1
Mette Stausland Istre,1 Karl Trygve Kalleberg,2 Camilla L Søraas,3 Kirsten B Holven,4,5
Stine M Ulven,4 Anette Hjartåker,4 Trond Haider,6 Fridtjof Lund-Johansen,7 John Arne Dahl,1
Haakon E Meyer,8,9 Arne Søraas1
For numbered aliations see AbA
end of the article Oj
Correspondence to: A Søraas To determine if daily supplementation with cod liver
arne@meg.no oil, a low dose vitamin D supplement, in winter,
(ORCID 0000-0003-1622-591X)
prevents SARS-CoV-2 infection, serious covid-19, or
Additional material is published
online only. To view please visit other acute respiratory infections in adults in Norway.
the journal online. D
ite this as: BMJ 2022;378:e071245 Quadruple blinded, randomised placebo controlled
http://dx.doi.org/10.1136/
trial.
bmj-2022-071245
Accepted: 19 July 2022 
Norway, 10 November 2020 to 2 June 2021.
PP
34 601 adults (aged 18-75 years), not taking daily
vitamin D supplements.
O
5 mL/day of cod liver oil (10 µg of vitamin D,
n=17 278) or placebo (n=17 323) for up to six months.
M OOM M
Four co-primary endpoints were predened: the rst
was a positive SARS-CoV-2 test result determined
by reverse transcriptase-quantitative polymerase
chain reaction and the second was serious covid-19,
dened as self-reported dyspnoea, admission to
hospital, or death. Other acute respiratory infections
were indicated by the third and fourth co-primary
endpoints: a negative SARS-CoV-2 test result and
self-reported symptoms. Side eects related to the
supplementation were self-reported. The fallback
method was used to handle multiple comparisons.
WA I AAy kW  I pI
Vitamin D has been suggested as having a role in the prevention of covid-19, but
most studies have been observational
A recent meta-analysis of 46 randomised controlled trials showed that vitamin
D supplementation decreased the risk of acute respiratory infections compared
with placebo, but the eect was small
WA I y A
Of 34 601 unselected adult participants, no dierence in the incidence of SARS-
CoV-2 infection, serious covid-19, or acute respiratory infections was found for
those randomised to daily supplements of low dose vitamin D (cod liver oil) or
placebo (corn oil) during the winter
The cod liver oil and placebo group had similar side eects, and only low grade
side eects were reported
the bmj  BMJ 2022;378:e071245 | doi: 10.1136/bmj-2022-071245

Supplementation with cod liver oil was not associated
with a reduced risk of any of the co-primary endpoints.
Participants took the supplement (cod liver oil or
placebo) for a median of 164 days, and 227 (1.31%)
participants in the cod liver oil group and 228 (1.32%)
participants in the placebo group had a positive
SARS-CoV-2 test result (relative risk 1.00, multiple
comparison adjusted condence interval 0.82 to
1.22). Serious covid-19 was identied in 121 (0.70%)
participants in the cod liver oil group and in 101
(0.58%) participants in the placebo group (1.20,
0.87 to 1.65). 8546 (49.46%) and 8565 (49.44%)
participants in the cod liver oil and placebo groups,
respectively, had ≥1 negative SARS-CoV-2 test results
(1.00, 0.97 to 1.04). 3964 (22.94%) and 3834
(22.13%) participants in the cod liver oil and placebo
groups, respectively, reported ≥1 acute respiratory
infections (1.04, 0.97 to 1.11). Only low grade side
eects were reported in the cod liver oil and placebo
groups.
OO
Supplementation with cod liver oil in the winter did
not reduce the incidence of SARS-CoV-2 infection,
serious covid-19, or other acute respiratory infections
compared with placebo.
 O
ClinicalTrials.gov NCT04609423.
Introduction
Vitamin D has received much attention during the
covid-19 pandemic for its potential role in preventing
and treating covid-19.1-9 Preclinical studies have
reported a role for vitamin D metabolites in the
immune responses to respiratory viruses, although
the mechanisms are not fully understood.10 Low
levels of 25-hydroxyvitamin D3 (25(OH)D3) have been
associated with an increased risk of acute respiratory
infections.11 A recent meta-analysis, examining 46
randomised controlled trials, concluded that vitamin
D supplementation (400-1000 IU/day or 10-25 µg/
day) decreased the risk of acute respiratory infections
compared with placebo.12
Serious covid-19 has been associated with increased
inammation with uncontrolled activation of immune
cells and excessive release of proinammatory
cytokines.13 Long chained omega 3 fatty acids,
1
RESEARCH
particularly eicosapentaenoic acid and docosahexaenoic
acid, have been reported to have anti-inammatory
eects.14-17 Ensuring adequate levels of these fatty acids
and vitamin D has been proposed as a cost eective
measure to prevent SARS-CoV-2 infection and serious
covid-19.13
Cod liver oil is a low dose vitamin D supplement with
eicosapentaenoic acid and docosahexaenoic acid. A
long tradition exists in Norway of taking cod liver oil
during the winter to prevent vitamin D deciency.
Therefore, we initiated the Cod Liver Oil for Covid-19
Prevention Study (CLOC), where participants were
randomised to receive cod liver oil or placebo (corn
oil) during the winter of 2020-21, and we examined
whether cod liver oil could prevent SARS-CoV-2
infection, serious covid-19, or other acute respiratory
infections.
Methods
CLOC was a randomised, parallel group treatment,
quadruple masked (participant, investigator,
outcomes assessor, and data analysts), two armed trial.
Supplement 1 provides details of the study protocol,
changes to the protocol, and the statistical analysis
plan. Ethical approval of the trial was obtained (30
September 2020), and the trial was registered in
ClinicalTrials.gov (22 October 2020) before recruitment
of participants. The statistical analysis plan was
registered in ClinicalTrials.gov (26 November 2021)
before the analysis and unblinding of the intervention.
rial population
Between 10 November 2020 and 13 April 2021,
adults (aged ≥18 years) with a Norwegian personal
identity number and electronic access to the secure
national digital governmental identication service,
were invited to participate in the trial through a media
campaign, and invitations were also sent to participants
of the Norwegian Covid-19 Cohort Study. Excluded
were people with prespecied diseases (including a
history of renal failure or dialysis, hypercalcaemia,
severe liver disease (cirrhosis), sarcoidosis, or other
granulomatous diseases (eg, granulomatosis with
polyangiitis (formerly Wegener’s granulomatosis)),
and previous covid-19), those who could not swallow
oil, those with reactions to sh or cod liver oil, or corn
oil, and those with indications for taking vitamin
D supplements (vegan, pregnant, aged >75 years).
Participants already taking cod liver oil or any other
supplements with vitamin D for ≥5 days/week were
also excluded, except for those with dark skin when all
participants were included, regardless of their use of
vitamin D supplements. Figure 1 shows the numbers
of eligible randomised participants and the number of
participants in the nal analyses.
ntervention
Participants were randomised in a 1:1 ratio to take
cod liver oil or placebo (corn oil). Both products were
oils in liquid form, and the recommended daily dosage
was 5 mL. The cod liver oil was avoured with lemon,
2 doi: 10.1136/bmj-2022-071245 | BMJ 2022;378:e071245 | the bmj
BMJ: first published as 10.1136/bmj-2022-071245 on 7 September 2022. Downloaded from http://www.bmj.com/ on 18 March 2024 by guest. Protected by copyright.
and the same lemon aroma was added to the placebo
oil. Both products were successfully blind tested by an
experienced taste panel (who could not distinguish
between the products) who routinely blind test each
batch of cod liver oil that is produced. Participants
were encouraged to take the supplement at the same
time each day, with a 5 mL measurement spoon or
tablespoon, according to the instructions they received
with the product (a picture of a tablespoon with 5 mL
of oil). For the cod liver oil, 5 mL of oil contained about
10 µg of vitamin D3 (400 IU), 1.2 g of long chained
omega 3 polyunsaturated fatty acids, including 0.4 g
of eicosapentaenoic acid and 0.5 g of docosahexaenoic
acid, 250 µg of vitamin A, and 3 mg of vitamin E. For
placebo, 5 mL of corn oil contained about 15.8 µg of
vitamin A and 3.8 mg of vitamin E (analysed levels of
vitamins A, D, and E in cod liver oil and placebo are
presented in sTable 1, supplement 2).
andomisation, blinding, and data storage
Randomisation was conducted at the Department of
Research Support, Oslo University Hospital, by sta
not involved in the trial (rounds of randomisation
are listed in sTable 2, supplement 2). Randomisation
was conducted as simple randomisation without
blocking or stratication because of the large study
population. A list of participants with their addresses
and group assignment (cod liver oil or placebo group)
was provided to a packaging company, which sent
cod liver oil or placebo to participants. Sta at the
packaging company were not involved in the trial, and
no individuals involved in the trial had access to the
list.
Participants and researchers involved in all phases
of the trial were blinded to the group assignment of
each participant. Unblinding was done when the
analysis of all co-primary endpoints was completed
(13 December 2021). The University of Oslo’s services
for sensitive data was used to collect, store, and
analyse the data.
Questionnaires
Participants completed baseline questionnaires
before they were randomised to receive cod liver oil or
placebo. The questionnaires covered personal data,
questions related to vitamin D, and other questions.
After randomisation, practical instructions were sent
to participants, followed by six (monthly) reporting
questionnaires with items on compliance with the
intervention, infection with SARS-CoV-2, acute
respiratory infections, vaccination for covid-19,
open question on side eects, and other questions
(sAppendix 1, supplement 2). Compliance was
dened as strict if >0.5 L of cod liver oil or placebo was
consumed, or cod liver oil or placebo was taken for
>2-3 months. Loose compliance was dened as >0.1 L
of cod liver oil or placebo consumed, cod liver oil or
placebo taken for >0-1 month, or cod liver oil or placebo
consumed for >1 day/week. Total participation time
for each participant was estimated from the earliest
reported start date of taking cod liver oil or placebo
 RESEARCH

BMJ: first published as 10.1136/bmj-2022-071245 on 7 September 2022. Downloaded from http://www.bmj.com/ on 18 March 2024 by guest. Protected by copyright.
166 024 Open invitation through media
Invitation through Norwegian covid-19 cohort*

39 853 7357
Willing to participate Willing to participate

47 210
Assessed for eligibility

12 469
Not meeting inclusion criteria
666 Particular diseases†
550 Previous covid-19
859 Cannot swallow oil
56 Reactions to cod liver or corn oil
1710 Indications for taking vitamin D supplement‡
11 317 Using cod liver oil or similar ≥5 days/week

34 741
Randomised

17 349 17 392
Allocated to cod liver oil Allocated to placebo

Follow-up (intervention) for 6 months Follow-up (intervention) for 6 months

Median 164 (range 0-193) days follow-up
14 789
Compliance, loose§ (85.6%)
11 959
Compliance, strict¶ (69.2%)
Median 164 (range 0-193) days follow-up
14 706
Compliance, loose§ (84.9%)
11 412
Compliance, strict¶ (66.2%)

71 69
Excluded from analysis Excluded from analysis
45 Positive SARS-CoV-2 test 49 Positive SARS-CoV-2 test
before randomisation before randomisation
26 Positive SARS-CoV-2 test in 20 Positive SARS-CoV-2 test in
rst 7 days of supplementation rst 7 days of supplementation

17 278 17 323
Analysed, intention to treat Analysed, intention to treat

Fig 1 | onsolidated tandards of eporting rials (OO) flow diagram of od iver Oil for ovid-19 Prevention tudy (O). *orwegian
ovid-19 ohort tudy is a population based open cohort established in March 2020. †ncluding history of renal failure or dialysis, hypercalcaemia,
severe liver disease (cirrhosis), sarcoidosis, or other granulomatous disease (eg, granulomatosis with polyangiitis (formerly Wegener’s
granulomatosis)). ‡egan, pregnant, ≥75 years old. §oose compliance: reported consuming >0.1  of cod liver oil or placebo, consuming cod liver
oil or placebo for >0-1 month, or consuming cod liver oil or placebo for >1 day/week. ¶trict compliance: reported consuming >0.5  of cod liver oil or
placebo or consuming cod liver oil or placebo for >2-3 months

until the latest reported nal date of taking cod liver
oil or placebo. If no start date was reported, the start
date was set as the randomisation date plus 14 days.
If no nal date was reported, the nal date was set as
the nal date of the intervention period (2 June 2021).
Side eects were categorised and graded according to
the Common Terminology Criteria for Adverse Events
(CTCAE). The rst questionnaire was sent out on 21
December 2020 and the last on 2 June 2021. The
University of Oslo’s web based solution Nettskjema
was used to distribute information and questionnaires
electronically.
ndpoints: covid-19 and other acute respiratory
infections
Four co-primary endpoints were assessed. The rst
co-primary endpoint was the incidence of a positive
SARS-CoV-2 nasopharyngeal or oropharyngeal
swab test determined by reverse transcriptase-
quantitative polymerase chain reaction in a Norwegian
microbiology laboratory reported to the Mandatory
Norwegian Surveillance System for Communicable
Diseases (MSIS). The second co-primary endpoint was
the incidence of serious covid-19 (MSIS conrmed
covid-19) with self-reported dyspnoea, or admission to

the bmj  BMJ 2022;378:e071245 | doi: 10.1136/bmj-2022-071245 3

RESEARCH
hospital or death. If data were missing for the variable
serious covid-19, participants were included in the
non-serious covid-19 outcome. Missing information
was checked against medical records connected to the
Norwegian Cause of Death Registry for information
on deaths. The third co-primary endpoint was the
incidence of participants with ≥1 negative SARS-CoV-2
test results recorded in MSIS. Most testing in Norway
during the trial was conducted after participants
showed symptoms of covid-19, and in our data >85% of
negative test results were accompanied by symptoms.
Thus having ≥1 negative SARS-CoV-2 test results was
used as an indication of having ≥1 acute respiratory
infections. The fourth co-primary endpoint was the
incidence of participants reporting ≥1 acute respiratory
infections. Missing information or unreported acute
respiratory infections were included in the non-acute
respiratory infections outcome during the intervention
period.
Prespecied secondary endpoints and exploratory
endpoints
Prespecied secondary endpoints (number of
participants admitted to hospital for covid-19 and
number of participants in the intensive care unit for
covid-19) were self-reported. Exploratory endpoints
included self-reported side eects, blinding of the
study supplement, and change in blood levels of
25(OH)D3 and omega 3 index over the study period
(from a subsample of the population).
Dried blood spot samples
To determine the eect of the intervention on levels of
25(OH)D3 and omega 3 fatty acids, capillary blood was
collected at home using dried blood spot samples in a
random subpopulation of participants. Samples were
obtained before and during supplementation with cod
liver oil or placebo and analysed by Vitas Analytical
Services (Oslo). In total, 945 participants were sent
kits twice, and 342 participants returned both kits.
Participants received the kits by post and took a fasting
blood sample from the ngertip, placing the drops of
blood directly onto Whatman 903 Protein Saver dried
blood spot cards. Participants then placed the dried
blood spot card in a light and airproof Ziploc bag with
a desiccant and posted it to Vitas Analytical services.
Samples were stored at −80°C until analysed after the
intervention period (2–9 months after the samples
were collected).
For analyses of 25(OH)D3, dried blood spot punches
(four circles, diameter 3.2 mm, with dried whole blood
on certied paper) of human whole blood were diluted
with water. After whole blood extraction, analytes
were extracted with 2-propanol containing an internal
standard. After analytes were extracted, samples were
centrifuged through a lter plate for removal of whole
blood debris. The eluate was injected into a Ultivo Triple
Quadrupole liquid chromatography-mass spectrometer
(Agilent Technologies, Santa Clara, CA), separated by
a Kinetex 2.6 µm C18 100 Å liquid chromatography
column 100×4.6 mm (Phenomenex, Torrance, CA)
4 doi: 10.1136/bmj-2022-071245 | BMJ 2022;378:e071245 | the bmj
BMJ: first published as 10.1136/bmj-2022-071245 on 7 September 2022. Downloaded from http://www.bmj.com/ on 18 March 2024 by guest. Protected by copyright.
(Vitas Analytical Services). The accuracy of the 25(OH)
D3 analyses was maintained by participation in the
Vitamin D External Quality Assessment Scheme
(DEQAS, sAppendix 2 and sTable 3, supplement 2).
For analyses of omega 3 fatty acids, two punches
of human whole blood were methylated with sodium
methylate. After methylation, fatty acid methyl esters
were extracted with hexane. After thorough mixing
and centrifugation, 3 µL of the aliquot were injected
into a gas chromatography-ame ionisation detector.
Gas chromatography-ame ionisation detection
was performed with an Agilent HP 7890A Gas
Chromatograph System (Agilent Technologies, Palo
Alto, CA). The fatty acid methyl esters were separated on
a TR-FRAME gas chromatography column (30 m×0.25
mm×0.25 µm lm column) from Thermo Scientic
(part No 260M142P) (Vitas Analytical Services).
aseline -o-2 antibody analysis
Randomly selected participants (n=1333) provided
whole blood samples to a local laboratory for analysis
of SARS-CoV-2 antibodies at baseline. A ow cytometer
based method was used to identify IgG antibodies
against SARS-CoV-2 derived recombinant antigens in
residual sera.18 Samples with antibodies against both
the receptor binding domain and the spike protein of
SARS-CoV-2 were considered positive.
tatistical analyses
Power calculation was done with the fallback
method, used to adjust for multiple testing.19 Sample
size calculations were based on our own unpublished
results from the Norwegian Covid-19 Cohort Study.
A signicance level (α) of 0.05 was divided between
the four co-primary endpoints (0.03, 0.018, 0.001,
and 0.001, respectively). The α levels were dierent
because the four endpoints were weighted dierently.
The rst and second (covid-19 related) co-primary
endpoints were assigned an α value of 0.03 and
0.018, respectively. Based on an expected incidence
of SARS-CoV-2 infection of 1%, a 20% reduction in the
incidence of SARS-CoV-2 infection in the intervention
group, and power of 70%, 65 000 participants were
required for the rst co-primary endpoint. Based on
an incidence of serious covid-19 of 0.25%, a 40%
reduction in serious covid-19 in the intervention
group, and power of 70%, 67 000 participants were
required for the second co-primary endpoint. Based
on the expected frequency of acute respiratory
infections of >30% and a threshold of 10% reduction
in acute respiratory infections, 23 000 participants
would need to be included for the third and fourth
co-primary endpoints with a power of >95%. An α
value of 0.001 was assigned for the third and fourth
co-primary endpoints. Multiple comparison adjusted
condence intervals are reported for the four co-
primary endpoints (97%, 98.2%, 99.9%, and 99.9%
condence intervals, respectively).
All four co-primary endpoints were analysed for the
relative risk of acquiring a condition using cod liver
oil versus placebo with the Wald test. The time to rst

occurrence of the co-primary endpoints was plotted
with the Kaplan-Meier approach. Logistic regression
and the Wald test were used in the subgroup analyses
(grouped by sex, age, body mass index, skin type,
exposure to sun from July to October 2020, use of
vitamin D supplements, vaccinated during the study
period, consumers of fatty sh, and strict compliance)
to assess the eect on the co-primary endpoints. These
ad hoc subgroup analyses were chosen as they could
aect (or cause a known dierence in) levels of 25(OH)
D3 or omega 3 fatty acids, or aect the incidence of
SARS-CoV-2 infection or serious covid-19.
The Wilcoxon signed rank test, the Mann-Whitney
test, and linear regression were used to compare
25(OH)D3 and omega 3 index levels and changes
between and within the cod liver oil and placebo
groups (α<0.05). Pearson’s χ2 test was used to examine
side eects and which treatment participants thought
they were assigned to in the cod liver oil and placebo
groups (α<0.05).
Participant and public involvement
The Norwegian Covid-19 Cohort Study had a user panel
that was involved in the planning of the CLOC study,
including setting the research agenda and planning of
the questionnaires.
esults
rial participants
Overall, 34 741 men and women were randomised to
receive cod liver oil or placebo, and 140 participants
were excluded from the analyses because of a positive
SARS-CoV-2 test result during the period from consent
to participation up to seven days after starting to
take cod liver oil or placebo. Participants took the
supplement (cod liver oil or placebo) for a median of
164 days. We included 17 278 and 17 323 participants
in the cod liver oil and placebo groups, respectively, in
the analyses (g 1).
More than half of participants were women (64.5%),
mean age was 44.9 years, and mean body mass index
was 26.1 at baseline (table 1). Most participants
(75.5%) did not use vitamin D supplements before
enrolling in the trial, 61.5% consumed fatty sh, and
39.8% reported ≤30 hours of exposure to the sun from
July to October 2020. Subsample analyses for SARS-
CoV-2 antibodies at baseline showed that 28 of 1333
participants (2.1%) had a positive antibody test result
(data not shown). During the intervention, 35.6% of
participants (6233 and 6097 in the cod liver oil and
placebo groups, respectively) reported receiving ≥1
doses of a SARS-CoV-2 vaccine (table 1).
od liver oil and covid-19
In total, 455 participants had a positive SARS-CoV-2
test result, with similar event rates in the cod liver oil
and placebo groups (227 (1.31%) and 228 (1.32%)
respectively; relative risk 1.00, 97.0% condence
interval 0.82 to 1.22, table 2). The Kaplan-Meier
curve showed similar rates of positive SARS-CoV-2 test
results in the cod liver oil and placebo groups (g 2).
the bmj  BMJ 2022;378:e071245 | doi: 10.1136/bmj-2022-071245
RESEARCH
BMJ: first published as 10.1136/bmj-2022-071245 on 7 September 2022. Downloaded from http://www.bmj.com/ on 18 March 2024 by guest. Protected by copyright.
Serious covid-19 was reported by 222 participants
(121 (0.70%) in the cod liver oil group and 101 (0.58%)
in the placebo group), all had dyspnoea, 17 were
admitted to hospital (eight in the cod liver oil group
and nine in the placebo group), and no participants
died. Of those admitted to hospital for covid-19, eight
participants (four in each group) were in the intensive
care unit. The relative risk of serious covid-19 was
1.20 (98.2% condence interval 0.87 to 1.65, table 2)
for the cod liver oil group compared with the placebo
group. Analyses stratied by sex, age, body mass
index, exposure to sun from July to October 2020, use
of vitamin D supplements, vaccinated during the study
period, consumers of fatty sh, and strict compliance
did not modify the eect of cod liver oil on having a
positive SARS-CoV-2 test result or serious covid-19
(sTable 4, supplement 2).
od liver oil and acute respiratory infections
Our results showed that 17 111 participants had ≥1
negative SARS-CoV-2 test results, with similar event
rates in the cod liver oil and placebo groups (8546
(49.46%) and 8565 (49.44%), respectively; relative
risk 1.00, 99.9% condence interval 0.97 to 1.04,
table 2). One or more acute respiratory infections
were reported by 7798 participants (3964 (22.94%)
and 3834 (22.13%) participants in the cod liver oil
and placebo groups, respectively). The relative risk
of having ≥1 acute respiratory infections was 1.04
(99.9% condence interval 0.97 to 1.11, table 2) for
the cod liver oil group compared with the placebo
group. Analyses stratied by sex, age, body mass
index, skin type, exposure to sun from July to October
2020, use of vitamin D supplements, vaccinated
during the study period, consumers of fatty sh, and
strict compliance did not appear to modify the eect
of cod liver oil on having ≥1 negative SARS-CoV-2 test
results or ≥1 acute respiratory infections (sTable 5 and
sTable 6, supplement 2).
lood levels of 25(OH)D3 and omega 3 index
Of 945 participants who were sent a dried blood spot
kit for measuring levels of 25(OH)D3 and omega 3 index
before and while taking the supplements, 342 returned
two complete samples (172 in the cod liver oil group
and 170 in the placebo group, table 3). From the rst to
the second measurement, participants in the cod liver
oil group had only slightly increased concentrations of
25(OH)D3 (median 4.4 nmol/L, 25th to 75th centiles
−14.4-23.3, P=0.06). Cod liver oil was observed to
prevent a reduction in 25(OH)D3 in winter, however,
as found in the placebo group (−12.5 nmol/L, −24.1-
4.1, P<0.001). In the cod liver oil group, the mean
concentration of 25(OH)D3 was increased by 15.0
nmol/L (95% condence interval 8.8 to 21.2, P<0.001)
and the omega 3 index by 1.9% (1.6 to 2.2, P<0.001)
compared with the placebo group. Our results showed
that 295 (86.3%) participants had concentrations of
25(OH)D3 ≥50 nmol/L before the intervention period
(before supplementation). During the intervention
period (during supplementation), 155 (90.1%) and
5
RESEARCH

ide eects and blinding of trial participants

BMJ: first published as 10.1136/bmj-2022-071245 on 7 September 2022. Downloaded from http://www.bmj.com/ on 18 March 2024 by guest. Protected by copyright.
able 1 | haracteristics of participants at baseline, according to randomisation to cod
liver oil or placebo group. Data are number (%) of participants unless stated otherwise Overall, 10.1% and 11.3% of participants in the cod
Overall od liver oil group Placebo group liver oil and placebo groups, respectively, reported ≥1
haracteristics (n=34 601) (n=17 278) (n=17 323) side eects while taking the supplements during the
Sex: intervention period (table 3). The most common side
Women 22 346 (64.6) 11 161 (64.6) 11 185 (64.6)
eects were mild gastrointestinal symptoms, classied
Men 12 254 (35.4) 6117 (35.4) 6137 (35.4)
Mean (SD) age (years) 44.9 (13.4) 45.0 (13.5) 44.9 (13.4)
as CTCAE grade 1. The side eects classied as CTCAE
Mean (SD) body mass index 26.1 (4.7) 26.1 (4.7) 26.1 (4.7) grade 2 were more common in the placebo group than
Smoking: in the cod liver oil group because of a higher number
Never 17 770 (51.4) 8906 (51.5) 8864 (51.2) of participants self-reporting low levels of vitamin D in
Past smoker 12 116 (35.0) 6025 (34.9) 6091 (35.2) the placebo group (n=36 v n=8, respectively). The other
Current smoker 2687 (7.8) 1340 (7.8) 1347 (7.8)
CTCAE grade 2 symptoms reported by participants
Chronic disease*:
No chronic disease 25 403 (73.4) 12 658 (73.3) 12 745 (73.6)
were similarly distributed in the cod liver oil (n=13)
≥1 chronic diseases 7669 (22.2) 3852 (22.3) 3817 (22.0) and placebo (n=11) groups and included heart
Parental ethnic origin: palpitations, allergic reactions, and gastrointestinal
Europe 32 831 (94.9) 16 441 (95.2) 16 390 (94.6) symptoms.
Asia 720 (2.1) 358 (2.1) 362 (2.1) In the last reporting questionnaire, 17 860 (51.6%)
Africa 217 (0.6) 108 (0.6) 109 (0.6)
participants responded to the question about which
Other 576 (1.7) 268 (1.6) 308 (1.8)
type of supplement they thought they had been taking.
Skin type:
Easily burnt 6453 (18.7) 3270 (18.9) 3183 (18.4) Of these, 7220 (78.6%) in the cod liver oil group and
Sometimes burnt to never burnt 25 809 (74.6) 12 895 (74.7) 12 914 (74.6) 7616 (87.8%) in the placebo group believed they had
Naturally tanned 695 (2.0) 334 (1.9) 361 (2.1) been taking a placebo or did not know, whereas 1966
Sun exposure from July to October 2020: (21.4%) in the cod liver oil group and 1058 (12.2%) in
≤30 hours 13 752 (39.8) 6924 (40.1) 6828 (39.4) the placebo group thought they had been taking cod
>30 hours 20 197 (58.4) 10 035 (58.1) 10 162 (58.6)
liver oil (table 3).
Vitamin D supplement use†:
No 26 130 (75.5) 13 092 (75.8) 13 038 (75.3)
Yes 7705 (22.3) 3799 (22.0) 3906 (22.5) iscussion
Fatty sh consumer‡: In this large, randomised, primary prevention trial,
No 12 714 (36.7) 6381 (36.9) 6333 (36.6) supplementation with cod liver oil, a low dose vitamin D
Yes 21 285 (61.5) 10 601 (61.4) 10 684 (61.7) supplement, was not associated with a reduction in the
Household count:
incidence of SARS-CoV-2 infection, serious covid-19,
1 5351 (15.5) 2703 (15.6) 2648 (15.3)
2 10 981 (31.7) 5477 (31.7) 5504 (31.8) or other acute respiratory infections compared with
≥3 16 979 (49.0) 8462 (48.9) 8517 (49.1) placebo. Only low grade side eects were reported, and
Children in household: fewer participants reported side eects in the cod liver
0 19 120 (55.3) 9549 (55.3) 9571 (55.3) oil group than in the placebo group.
1 4943 (14.3) 2507 (14.5) 2436 (14.1) The null ndings of supplementation with cod liver
≥2 9190 (26.5) 4543 (26.3) 4647 (26.8)
oil on the risk of SARS-CoV-2 infection and serious
Education:
Primary or lower secondary school§ 895 (2.6) 466 (2.7) 429 (2.5) covid-19 in our trial are in line with the results of
Secondary school or vocational 6988 (20.2) 3469 (20.1) 3519 (20.3) a mendelian randomisation study that found no
programmes¶ association between concentrations of 25(OH)D3 and
Higher education 22 529 (65.1) 11 302 (65.4) 11 227 (64.8) risk of SARS-CoV-2 infection or serious covid-19, and
Household income (NOK):
the authors concluded that vitamin D supplementation
≤1 million 18 290 (52.9) 9108 (52.6) 9182 (53.0)
would have had no preventive eect.7 Our ndings are
>1 million 14 444 (41.7) 7274 (42.1) 7170 (41.4)
Occupational status: also similar to the results of a large trial on vitamin
Working or student 28 634 (82.8) 14 325 (82.9) 14 309 (82.6) D and covid-19 (published as a preprint), although
Retired 2566 (7.4) 1294 (7.5) 1272 (7.3) participants had lower levels of 25(OH)D3 initially than
Unemployed, sick leave, or social 3253 (9.4) 1595 (9.2) 1658 (9.6) our subsample and were given larger vitamin D doses.20
security
Our null ndings contrast with a recent small double
Other 1352 (3.9) 668 (3.9) 684 (3.9)
Vaccinated during study period** 12 330 (35.6) 6233 (36.1) 6097 (35.2)
blind, placebo controlled trial suggesting that vitamin
SD=standard deviation; NOK=Norwegian kroner (1 Kr; £0.09; €0.10; $0.10). D supplements prevented covid-19 in people at high
Data were missing for 1.7-5.4% of participants except for the variable education where data were missing for risk of SARS-CoV-2 infection.21 The supplementation
11.9% of participants.
*One or more of these chronic conditions: heart disease, hypertension, lung disease, asthma, diabetes, cancer, regimen diered from ours, however, with 4000 IU of
and other, or treated with immunosuppressants. vitamin D given every day for one month, and 67% of
†Taking vitamin D supplements (including cod liver oil) ≥5 days/week was an exclusion criterion but individuals
with a lower frequency of use were included.
participants had 25(OH)D3 concentrations <50 nmol/L
‡Consuming fatty sh ≥1-2 days/week or ≥1-3 slices of bread with fatty sh, or both. at the start of the trial. Our null ndings also contrast
§≤10 years of school (seven years of primary school, three years of lower secondary school). our own unpublished, preliminary unadjusted results
¶Upper secondary school or vocational programmes (usually about three years).
**Reported having ≥1 SARS-CoV-2 vaccines during the intervention period. (Norwegian Covid-19 Cohort Study), indicating that
participants taking cod liver oil had a reduced risk
123 (72.4%) participants in the cod liver oil and of developing covid-19 and of being admitted to
placebo groups, respectively, had concentrations ≥50 hospital for covid-19 than non-users. Furthermore,
nmol/L. two large observational studies (app based European/

6 doi: 10.1136/bmj-2022-071245 | BMJ 2022;378:e071245 | the bmj

 RESEARCH

BMJ: first published as 10.1136/bmj-2022-071245 on 7 September 2022. Downloaded from http://www.bmj.com/ on 18 March 2024 by guest. Protected by copyright.
able 2 | bsolute and relative risk, and condence intervals, for rst, second, third, and fourth co-primary endpoints, according to randomisation to
cod liver oil or placebo group, in intention-to-treat analyses
od liver oil group (n=17 278) Placebo group (n=17 323)
Overall (n=34 601) bsolute risk bsolute risk
o-primary endpoint o (%) o (% (*)) o (% (*)) elative risk (*) P value†
ovid-19
First: SARS-CoV-2 positive test result 455 (1.32) 227 1.31 (1.13 to 1.50) 228 1.32 (1.13 to 1.50) 1.00 (0.82 to 1.22) 0.98
Second: serious covid-19‡ 222 (0.64) 121 0.70 (0.55 to 0.85) 101 0.58 (0.45 to 0.72) 1.20 (0.87 to 1.65) 0.17
cute respiratory infections
Third: ≥1 SARS-CoV-2 negative test results 17 111 (49.45) 8546 49.46 (48.21 to 50.71) 8565 49.44 (48.19 to 50.69) 1.00 (0.97 to 1.04) 0.97
Fourth: ≥1 self-reported acute respiratory 7798 (22.54) 3964 22.94 (21.89 to 24.00) 3834 22.13 (21.09 to 23.17) 1.04 (0.97 to 1.11) 0.07
infections
*First and second co-primary endpoints (covid-19), 97.0% and 98.2% condence interval, respectively; third and fourth co-primary endpoints (acute respiratory infections), 99.9% condence
interval.
†Logistic procedure P value for dierence between cod liver oil and placebo groups determined with the Wald test.
‡SARS-CoV-2 positive test result and self-reported dyspnoea (n=222), admission to hospital (n=17, eight in the cod liver oil group and nine in the placebo group), or death (n=0). Data were
missing for n=17 (13 in the cod liver oil group and four in the placebo group) for the variable serious covid-19; these were included in the non-serious covid-19 outcome.

American study and UK Biobank study) have found an
association between the use of vitamin D supplements
and reduced risk of covid-19.1 22
A meta-analysis described a protective eect of
vitamin D supplements against acute respiratory
infections, with the strongest eect for supplement
doses of 400-1000 IU/day for up to a year.12 In a
more recent meta-analysis (published as a preprint),
however, the authors questioned these initial results
because clustering was not accounted for in one of
the cluster randomised controlled trials included.
The authors did a secondary analysis of these
data, accounting for clustering in the randomised
controlled trial, and the updated meta-analysis
showed no protective eect of vitamin D supplements
on acute respiratory infections.23 This nding is in
line with our trial of no protective eect of vitamin
D supplementation against acute respiratory
infections.
In our trial, 86% of participants in the subsample with
dried blood spot tests had 25(OH)D3 concentrations
≥50 nmol/L before the trial started, which has been
suggested as an adequate level.23-25 Thus the possibility
that an eect of supplementation with vitamin D on
the risk of SARS-CoV-2 infection, serious covid-19, and
other acute respiratory infections was missed because
of adequate concentrations of 25(OH)D3 at the start of
1.000
Probability of not being
infected with SARS-CoV-2
the trial cannot be excluded. We found no dierence
in the relative risk for the co-primary endpoints when
stratied by factors associated with levels of 25(OH)D3
before the trial started (such as exposure to sun from
July to October 2020, use of vitamin D supplements, and
consuming fatty sh). The proportion of participants
with vitamin D deciency (25(OH)D3 <30 nmol/L) in
the trial population, however, was most likely low.
Our trial had a practical and realistic approach to
supplementation with vitamin D for the prevention of
covid-19 and other acute respiratory infections, testing
whether those not taking vitamin D supplements at the
start of the trial would benet from supplementation
during the winter. Widespread testing for 25(OH)D3
levels and only providing supplements for those with
low levels would require a dierent study design.
Few studies have examined omega 3 fatty acids and
the risk of SARS-CoV-2 infection, serious covid-19, and
other acute respiratory infections. The NutriNet-Santé
cohort found no association between dietary intake of
omega 3 fatty acids and susceptibility to covid-19.26
Conversely, others have seen an association between
omega 3 supplementation and reduced risk of
covid-191 and upper respiratory tract infections.27
Also, an inverse association between the omega 3
index in blood and death from covid-19 has been
reported.28 The eect of vitamins A and E, also present
in cod liver oil, on SARS-CoV-2 infection, serious
covid-19, and other acute respiratory infections is
not known. Vitamin D has been suggested to reduce

Cod liver oil

Placebo
the risk of severe asthma exacerbations in those with
0.995 mild to moderate asthma,29 whereas a Norwegian
study found an increase in the incidence of adult onset
asthma with the use of cod liver oil.30 Vitamin A levels
0.990
in the cod liver oil used in that study were more than
three times the daily amount provided by the cod liver
0.985 oil in our study, however. We believe it is unlikely that
vitamin A or E would have masked any eect of vitamin
0.980 D or omega-3 fatty acids on covid-19 disease or other
0 50 100 150 200 acute respiratory infections.1 31
Intervention period (days) Only low grade side eects were reported in our trial.
Fig 2 | Kaplan-Meier plot of the probability of a positive -o-2 test result for More side eects were reported by participants in the
participants in the cod liver oil (n=17 278) and placebo (n=17 323) groups during the placebo group than in the cod liver oil group, including
intervention period low levels of vitamin D.

the bmj  BMJ 2022;378:e071245 | doi: 10.1136/bmj-2022-071245 7

RESEARCH

BMJ: first published as 10.1136/bmj-2022-071245 on 7 September 2022. Downloaded from http://www.bmj.com/ on 18 March 2024 by guest. Protected by copyright.
able 3 | xploratory endpoints; side eects, blinding, and measured compliance according to randomisation to cod liver oil or placebo group. Data are
median (25th to 75th centiles) or number (%) unless stated otherwise
Overall (n=34 601) od liver oil group (n=17 278) Placebo group (n=17 323) P value
Measured compliance, from dried blood spots of a subsample*
25-hydroxyvitamin D3 (nmol/L):
Before supplementation 70.5 (56.7-92.3) 66.9 (52.2-91.0) 73.3 (59.6-92.7) 0.04†
During supplementation 67.9 (54.0-85.6) 74.1 (60.1-88.0) 62.8 (48.2-81.6) <0.001†
Change −3.6 (−20.9-14.4) 4.4 (−14.4-23.3) −12.5 (−24.1-4.1)‡‡ <0.001†
Omega 3 index (%):
Before supplementation 4.6 (3.7-5.7) 4.6 (3.7-5.5) 4.6 (3.7-5.8) 0.62†
During supplementation 5.1 (3.8-6.5) 6.2 (5.3-7.4) 4.1 (3.4-5.0) <0.001†
Change 0.3 (−0.7-1.7) 1.5 (0.4-2.5)‡‡ −0.5 (−1.1-0.1)‡‡ <0.001†
Side eects
Reported ≥1 side eects 3708 (10.7) 1742 (10.1) 1966 (11.3) <0.001‡
Grade§:
1 3640 (10.5) 1721 (10.0) 1919 (11.1) <0.001‡
2¶ 68 (0.2) 21 (0.1) 47 (0.3) 0.002‡
Most commonly self-reported:
Nausea, vomiting 1519 (4.4) 694 (4.0) 825 (4.8) <0.001‡
Regurgitation, burping 854 (2.5) 420 (2.4) 434 (2.5) 0.68‡
Stomach symptoms** 826 (2.4) 369 (2.1) 457 (2.6) 0.002‡
Reflux 772 (2.2) 384 (2.2) 388 (2.2) 0.94‡
Response to question “What supplement did you think you were taking?”††
Cod liver oil 3024 (16.9) 1966 (21.4) 1058 (12.2) <0.001‡
Placebo 11 458 (64.2) 5364 (58.4) 6094 (70.3) <0.001‡
Do not know 3378 (18.9) 1856 (20.2) 1522 (17.5) <0.001‡
*Subsample of 342 participants (cod liver oil group n=172, placebo group n=170) with dried blood spot samples from before randomisation (before supplementation) and during the
intervention period (during supplementation).
†Mann-Whitney U test, cod liver oil versus placebo group.
‡Pearson χ2 test, cod liver oil versus placebo group.
§Graded according to the Common Terminology Criteria for Adverse Events (CTCAE).
¶Of the CTCAE grade 2 side eects, self-reported low vitamin D levels were n=8 in the cod liver group and n=36 in the placebo group.
**Stomach symptoms included stomach pain, diarrhoea, and constipation.
††Answered by 17 860 (51.6%) participants.
‡‡Signicant change (Wilcoxon signed rank test) from before to during supplementation, P<0.001.

trengths and limitations of this trial
Limitations of our trial include self-reported data
for two of the four endpoints: dyspnoea, dening
serious covid-19, and self-reported acute respiratory
infections. Self-experienced symptoms are important
for participants, however, and the objective MSIS
based endpoints corroborated these results.
Compliance was self-reported, and therefore we had
no data on compliance from participants not returning
our questionnaires. Hence we could not distinguish
between not responding to the questionnaires and
being compliant with the intervention. However,
the results were comparable for the strict compliant
subgroup and the whole trial population.
The median intervention time was relatively short
at 164 days, and we do not have data on the possible
longer term eects of cod liver oil. Also, we could not
distinguish between the potential eect of vitamin D
and eicosapentaenoic acid or docosahexaenoic acid,
or explore a dose-response relation. Concentrations of
25(OH)D3 and omega-3 index were only available for
a small subsample of participants and thus we could
not study how levels of 25(OH)D3 at the start of the
trial were related to the risk of SARS-CoV-2 infection
and other acute respiratory infections. The available
25(OH)D3 results indicated that our trial population
seemed to have adequate levels of 25(OH)D3 at
inclusion in the trial.
We aimed to include 80 000 participants in our trial
but we could only include 34 601. Because of fewer
covid-19 incident cases than expected (455 instead
of 650), the trial was slightly underpowered to detect
a 20% reduction in the incidence of SARS-CoV-2
infection. Serious covid-19 was more prevalent than
anticipated, however, and the trial was adequately
powered for the second, third and fourth co-primary
endpoint despite the reduced numbers of participants
enrolled in the trial.
Our trial had several strengths, including a large
general adult population that did not use vitamin D
supplements regularly before the start of the trial,
implying that our vitamin D supplementation regimen
was realistic for testing whether this population would
benet from supplements during the winter. We found
good compliance with the study supplement among
participants, and blinding was successful because
most participants thought they had been taking
a placebo or did not know. The SARS-CoV-2 swab
test, analysed by reverse transcriptase-quantitative
polymerase chain reaction in an accredited Norwegian
microbiology laboratory, was the basis for the rst and
third co-primary endpoints (positive and negative tests,
respectively). Also, analysis of SARS-CoV-2 antibodies
in a subsample of participants at baseline conrmed
that only 2.1% had been infected with SARS-CoV-2
previously.
onclusions
Daily supplementation with cod liver oil, a low dose
vitamin D, eicosapentaenoic acid, and docosahexaenoic

8 doi: 10.1136/bmj-2022-071245 | BMJ 2022;378:e071245 | the bmj


acid supplement, for six months during the SARS-CoV-2
pandemic among Norwegian adults, did not reduce the
incidence of SARS-CoV-2 infection, serious covid-19, or
other acute respiratory infections. Only low grade side
eects were reported.
HO FFO
1
Department of Microbiology, Oslo University Hospital, Norway
2
Age Labs AS, Oslo, Norway
3
Department of Occupational Medicine, Oslo University Hospital,
Oslo, Norway
4
Institute of Basic Medical Sciences, Department of Nutrition,
University of Oslo, Oslo, Norway
5
Norwegian National Advisory Unit on Familial
Hypercholesterolaemia, Department of Endocrinology, Morbid
Obesity, and Preventive Medicine, Oslo University Hospital, Oslo,
Norway
6
Health Economics-Medical Statistics Trond Haider, Oslo, Norway
7 results through the website https://www.transtudien.no/, they will
Department of Immunology, University of Oslo and Oslo University
Hospital, Oslo, Norway
8
Department of Physical Health and Ageing, Norwegian Institute of
Public Health, Oslo, Norway
9
Department of Community Medicine and Global Health, University
of Oslo, Oslo, Norway
We thank all participants for contributing to the trial every morning by
taking the cod liver oil or placebo and completing the questionnaires;
the user panel of the Norwegian Covid-19 Cohort Study for their
involvement in the planning of the CLOC study; and the following
contributors to the project: statistician Inge Olsen, Department
of Research Support, Oslo University Hospital, for discussions on
study design and conducting the randomisation; Inger Tvenning,
Department of Research Support, Oslo University Hospital, for
practical work with blinding and unblinding; and Kay Frode Hofstad,
Bring AS, who successfully led the work of delivering the tens of
thousands of bottles of cod liver oil or placebo to participants.
Contributors: AS, KTK, and CLS conceptualised the trial. SHB, ABN,
KTK, CLS, KBH, SMU, AH, JAD, HEM, and AS designed the trial. All
authors acquired, analysed, or interpreted the data. SHB, ABN, and TH
curated the data and did the statistical analyses. SHB and ABN draed
the manuscript. ME-D, PH, MSI, KTK, CLS, KBH, SMU, AH, TH, FL-J, JAD,
HEM, and AS critically revised the manuscript for important intellectual
content. MSI provided administrative and technical support. KBH,
SMU, AH, JAD, HEM, and AS supervised. All authors approved the nal
manuscript and work. SHB and ABN contributed equally to this article
and act as guarantors. The corresponding author, AS, attests that all
listed authors meet authorship criteria and that no others meeting the
criteria have been omitted.
Funding: This work was funded by Orkla Health AS, the manufacturer
of Möller’s Tran, the cod liver oil used in the trial. Orkla Health delivered
cod liver oil or placebo to the trial and had the right to comment on the
manuscript content. It had no role in the conduct of the trial, collection
of data, management, or analysis of the data, nor preparation of the
manuscript. Orkla Health also had no influence on the decision to
submit the manuscript for publication or which journal the manuscript
was submitted to. The trial was also funded by Oslo University Hospital
and the University of Oslo; they had no role in the trial.
Competing interests: All authors have completed the ICMJE
uniform disclosure form at www.icmje.org/disclosure-of-interest/
and declare: support from Orkla Health AS, Oslo University Hospital,
and the University of Oslo for the submitted work. During the past
three years, KBH has received research grants or personal fees from
Olympic Seafood, Amgen, and Sano, not related to the content of
this manuscript. SMU has received a research grant from Olympic
Seafood during the past three years, not related to the content of
this manuscript. AS and KTK are employed by Age Laboratories AS, a
company developing SARS-CoV-2 diagnostics, and FL-J has received
grants from Helse-SørØst for developing SARS-CoV-2 diagnostics,
not related to the content of this manuscript. The authors declare; no
support from any organisation for the submitted work (except from the
funders); no nancial relationship with any organisations that might
have an interest in the submitted work in the previous three years; no
other relationships or activities that could appear to have influenced
the submitted work.
Ethical approval: All participants signed an electronic informed
consent form. All procedures involving participants were approved
the bmj  BMJ 2022;378:e071245 | doi: 10.1136/bmj-2022-071245
RESEARCH
BMJ: first published as 10.1136/bmj-2022-071245 on 7 September 2022. Downloaded from http://www.bmj.com/ on 18 March 2024 by guest. Protected by copyright.
by the Norwegian Regional Committee for Medical Research Ethics
(REK-172796) and by the Data Protection Ocer at Oslo University
Hospital following the European GDPR. The trial was carried out
according to the guidelines in the Declaration of Helsinki.
Data sharing: Individual level data from the trial for the purposes
outlined in the consent form can be shared with other researchers in
a timely fashion. The data are regulated under the European GDPR
regulative and sharing of data must be approved by the Data Protection
Ocer at Oslo University Hospital. The data dictionary, informed
consent form, and analytic code will be made available at: https://
oslo-universitetssykehus.no/kliniske-studier/forebygging-av-covid-
19-med-tran at the time of publication. Data will be made available for
researchers whose proposed use of the data has been approved.
The lead authors (SHB and ABN) arm that this manuscript is an
honest, accurate, and transparent account of the trial being reported;
that no important aspects of the trial have been omitted; and that any
discrepancies from the trial as planned (and, if relevant, registered)
have been explained.
Dissemination to participants and related patient and public
communities: Participants of the CLOC study will be informed of the
be sent details of the results in a study newsletter, and we expect
interest from the media who will disseminate the results of the trial to
a broader audience.
Provenance and peer review: Not commissioned; externally peer
reviewed.
This is an Open Access article distributed in accordance with the
Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license,
which permits others to distribute, remix, adapt, build upon this work
non-commercially, and license their derivative works on dierent
terms, provided the original work is properly cited and the use is non-
commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
1 Louca P, Murray B, Klaser K, et al. Modest eects of dietary
supplements during the COVID-19 pandemic: insights from 445
850 users of the COVID-19 Symptom Study app. BMJ Nutr Prev
Health 2021;4:149-57. doi:10.1136/bmjnph-2021-000250
2 Oscanoa TJ, Amado J, Vidal X, Laird E, Ghashut RA, Romero-Ortuno R.
The relationship between the severity and mortality of SARS-CoV-2
infection and 25-hydroxyvitamin D concentration - a metaanalysis.
Adv Respir Med 2021;89:145-57. doi:10.5603/ARM.a2021.0037
3 Kaya MO, Pamukçu E, Yakar B. The role of vitamin D deciency on
COVID-19: a systematic review and meta-analysis of observational
studies. Epidemiol Health 2021;43:e2021074. doi:10.4178/epih.
e2021074
4 Bassatne A, Basbous M, Chakhtoura M, El Zein O, Rahme
M, El-Hajj Fuleihan G. The link between COVID-19
and VItamin D (VIVID): A systematic review and meta-
analysis. Metabolism 2021;119:154753. doi:10.1016/j.
metabol.2021.154753
5 Wise J. Covid-19: Evidence is lacking to support vitamin D’s role in
treatment and prevention. BMJ 2020;371:m4912. doi:10.1136/bmj.
m4912
6 Chen J, Mei K, Xie L, et al. Low vitamin D levels do not aggravate
COVID-19 risk or death, and vitamin D supplementation does not
improve outcomes in hospitalized patients with COVID-19: a meta-
analysis and GRADE assessment of cohort studies and RCTs. Nutr
J 2021;20:89. doi:10.1186/s12937-021-00744-y
7 Butler-Laporte G, Nakanishi T, Mooser V, et al. Vitamin D and
COVID-19 susceptibility and severity in the COVID-19 Host
Genetics Initiative: A Mendelian randomization study. PLoS
Med 2021;18:e1003605. doi:10.1371/journal.pmed.1003605
8 Talaei M, Faustini S, Holt H, et al. Determinants of pre-vaccination
antibody responses to SARS-CoV-2: a population-based longitudinal
study (COVIDENCE UK). BMC Med 2022;20:87. doi:10.1186/
s12916-022-02286-4
9 Holt H, Talaei M, Greenig M, et al. Risk factors for developing
COVID-19: a population-based longitudinal study (COVIDENCE
UK). Thorax 2021;thoraxjnl-2021-217487. doi:10.1136/
thoraxjnl-2021-217487
10 Greiller CL, Martineau AR. Modulation of the immune response
to respiratory viruses by vitamin D. Nutrients 2015;7:4240-70.
doi:10.3390/nu7064240
11 Pham H, Rahman A, Majidi A, Waterhouse M, Neale RE. Acute
respiratory tract infection and 25-hydroxyvitamin D concentration:
a systematic review and meta-analysis. Int J Environ Res Public
Health 2019;16:E3020. doi:10.3390/ijerph16173020
12 Jollie DA, Camargo CAJr, Sluyter JD, et al. Vitamin D supplementation
to prevent acute respiratory infections: a systematic review and
meta-analysis of aggregate data from randomised controlled trials.
Lancet Diabetes Endocrinol 2021;9:276-92. doi:10.1016/S2213-
8587(21)00051-6
9
RESEARCH
13 Story MJ. Essential suciency of zinc, ω-3 polyunsaturated fatty acids,
vitamin D and magnesium for prevention and treatment of COVID-19,
diabetes, cardiovascular diseases, lung diseases and cancer.
Biochimie 2021;187:94-109. doi:10.1016/j.biochi.2021.05.013
14 Wei Y, Meng Y, Li N, Wang Q, Chen L. The eects of low-ratio n-6/n-3
PUFA on biomarkers of inflammation: a systematic review and meta-
analysis. Food Funct 2021;12:30-40. doi:10.1039/D0FO01976C
15 Zárate R, El Jaber-Vazdekis N, Tejera N, Pérez JA, Rodríguez C.
Signicance of long chain polyunsaturated fatty acids in human health.
Clin Transl Med 2017;6:25. doi:10.1186/s40169-017-0153-6
16 Jiang J, Li K, Wang F, et al. Eect of marine-derived n-3
polyunsaturated fatty acids on major eicosanoids: a systematic
review and meta-analysis from 18 randomized controlled trials. PLoS
One 2016;11:e0147351. doi:10.1371/journal.pone.0147351
17 Kiecolt-Glaser JK, Belury MA, Andridge R, Malarkey WB, Hwang BS,
Glaser R. Omega-3 supplementation lowers inflammation in healthy
middle-aged and older adults: a randomized controlled trial. Brain
Behav Immun 2012;26:988-95. doi:10.1016/j.bbi.2012.05.011
18 Holter JC, Pischke SE, de Boer E, et al. Systemic complement
activation is associated with respiratory failure in COVID-19
hospitalized patients. Proc Natl Acad Sci U S A 2020;117:25018-25.
doi:10.1073/pnas.2010540117
19 US Department of Health and Human Services. Food and Drug
Administration, Center for Drug Evaluation and Research (CDER),
and Center for Biologics Evaluation and Research (CBER). Multiple
Endpoints in Clinical Trials, Guidance for Industry.https://www.fda.
gov/media/102657/.
20 Jollie DA, Holt H, Greenig M, et al. Vitamin D supplements
for prevention of Covid-19 or other acute respiratory
infections: a phase 3 randomized controlled trial
(CORONAVIT).medRxiv 2022:2022.03.22.22271707.
doi:10.1101/2022.03.22.22271707
21 Villasis-Keever MA, López-Alarcón MG, Miranda-Novales G, et
al. Ecacy and safety of vitamin D supplementation to prevent
COVID-19 in frontline healthcare workers. a randomized
clinical trial. Arch Med Res 2022;53:423-30. doi:10.1016/j.
arcmed.2022.04.003
22 Ma H, Zhou T, Heianza Y, Qi L. Habitual use of vitamin D supplements
and risk of coronavirus disease 2019 (COVID-19) infection: a
prospective study in UK Biobank. Am J Clin Nutr 2021;113:1275-81.
doi:10.1093/ajcn/nqaa381
10
BMJ: first published as 10.1136/bmj-2022-071245 on 7 September 2022. Downloaded from http://www.bmj.com/ on 18 March 2024 by guest. Protected by copyright.
23 Bolland MJ, Avenell A, Grey A, et al. Vitamin D and
acute respiratory infection: secondary analysis of a
previous randomised controlled trial and updated meta-
analyses.medRxiv 2022:2022.02.03.22270409.
doi:10.1101/2022.02.03.22270409
24 Manson JE, Brannon PM, Rosen CJ, Taylor CL. Vitamin D deciency
- is there really a pandemic?N Engl J Med 2016;375:1817-20.
doi:10.1056/NEJMp1608005
25 Nordic Council of Ministers, Nordic Council of Ministers Secretariat.
Nordic Nutrition Recommendations, 2012: Integrating nutrition and
physical activity. https://www.norden.org/en/publication/nordic-
nutrition-recommendations-2012.
26 Deschasaux-Tanguy M, Srour B, Bourhis L, et al, SAPRIS-SERO study
group. Nutritional risk factors for SARS-CoV-2 infection: a prospective
study within the NutriNet-Santé cohort. BMC Med 2021;19:290.
doi:10.1186/s12916-021-02168-1
27 Raposo SE, Fondell E, Ström P, et al. Intake of vitamin C, vitamin
E, selenium, zinc and polyunsaturated fatty acids and upper
respiratory tract infection-a prospective cohort study. Eur J Clin
Nutr 2017;71:450-7. doi:10.1038/ejcn.2016.261
28 Asher A, Tintle NL, Myers M, Lockshon L, Bacareza H, Harris WS.
Blood omega-3 fatty acids and death from COVID-19: A pilot study.
Prostaglandins Leukot Essent Fatty Acids 2021;166:102250.
doi:10.1016/j.plefa.2021.102250
29 Martineau AR, Cates CJ, Urashima M, et al. Vitamin D for
the management of asthma. Cochrane Database Syst
Rev 2016;9:CD011511. doi:10.1002/14651858.CD011511.pub2
30 Mai X-M, Langhammer A, Chen Y, Camargo CAJr. Cod liver oil intake
and incidence of asthma in Norwegian adults--the HUNT study.
Thorax 2013;68:25-30. doi:10.1136/thoraxjnl-2012-202061
31 Vlieg-Boerstra B, de Jong N, Meyer R, et al. Nutrient supplementation
for prevention of viral respiratory tract infections in healthy subjects:
A systematic review and meta-analysis. Allergy 2022;77:1373-88.
doi:10.1111/all.15136
Web appendix 1: Supplement 1—study protocol and
data analysis plan
Web appendix 2: Supplement 2—supplemental
online content
doi: 10.1136/bmj-2022-071245 | BMJ 2022;378:e071245 | the bmj